KPNA2 promotes the progression of gastric cancer by regulating the alternative splicing of related genes.

RNA-binding proteins (RBPs) play critical roles in genome regulation. In this study, we explored the latent function of KPNA2, which is an essential member of the RBP family, in the regulation of alternative splicing (AS) in gastric cancer (GC). We analyzed the role of KPNA2 in regulating differential expression and AS via RNA sequencing (RNA-seq) and improved RNA immunoprecipitation sequencing (iRIP-seq). Clinical specimens were used to analyze the associations between KPNA2 expression and clinicopathological characteristics. CCK8 assays, transwell assays and wound healing assays were performed to explore the effect of KPNA2/WDR62 on GC cell progression. KPNA2 was shown to be highly expressed in GC cells and tissues and associated with lymph node metastases. KPNA2 promoted the proliferation, migration and invasion of GC cells and primarily regulated exon skipping, alternative 3's splice sites (A3SSs), alternative 5' splice sites (A5SSs), and cassette exons. We further revealed that KPNA2 participated in biological processes related to cell proliferation, and the immune response in GC via the regulation of transcription. In addition, KPNA2 preferentially bound to intron regions. Notably, KPNA2 regulated the A3SS AS mode of WDR62, and upregulation of WDR62 reversed the KPNA2 downregulation-induced inhibition of GC cell proliferation, migration and invasion. Finally, we discovered that the AS of immune-related molecules could be regulated by KPNA2. Overall, our results demonstrated for the first time that KPNA2 functions as an oncogenic splicing factor in GC that regulated the AS and differential expression of GC-related genes, and KPNA2 may be a potential target for GC treatment.

Elemental diet preventative effects for adverse events during chemotherapy in patients with esophageal cancer - A systematic review and meta-analysis.

Introduction: The effectiveness of an elemental diet (ED) for preventing adverse events (AEs) during chemotherapy for patients with esophageal cancer (EC) remains unclear. The aim of this meta-analysis was to comprehensively assess the efficacy of ED for preventing AE in EC patients during chemotherapy. Medline (via PubMed), Embase, the Cochrane Library, and Web of Science were searched to retrieve prospective and randomized studies published before April 12, 2023. The odds ratio (OR) of each AE was calculated using Review Manger 5.4.1. The risk of bias was assessed, and a random effect model-based meta-analysis was used to analyze the available data. Four prospective and randomized studies involving 237 patients were identified after a systematic search. Regarding gastrointestinal toxicities, the findings indicated a trend toward a decrease in the risk of mucositis (OM) (OR = 0.54, 95 % CI: 0.25-1.14), constipation (OR = 0.87, 95 % CI: 0.49-1.53), and anorexia (OR = 0.99, 95 % CI: 0.32-3.05), as well as an increasing trend in the risk of diarrhea (OR = 1.48, 95 % CI: 0.79-2.79), among patients treated with ED. However, none of these reached statistical significance. For hematological toxicities, the risk of all-grade neutropenia (OR = 0.28, 95 % CI: 0.14-0.57), grade ≥ 2 leucopenia (OR = 0.43, 95 % CI: 0.22-0.84), grade ≥ 2 neutropenia (OR = 0.34, 95 % CI: 0.17-0.67), and grade ≥ 3 neutropenia (OR = 0.28, 95 % CI: 0.12-0.63) was significantly decreased. There is no firm evidence confirming the preventive effect of an ED against OM or diarrhea. However, an ED may potentially be helpful in preventing neutropenia and leucopenia.

Introducción: La efectividad de una dieta elemental (DE) para prevenir eventos adversos (EA) durante la quimioterapia en pacientes con cáncer de esófago (CE) sigue sin estar clara. Este metaanálisis evalúa la eficacia de DE para prevenir EA en pacientes con CE durante quimioterapia. Se realizaron búsquedas en Medline (con PubMed), Embase, Biblioteca Cochrane y Web of Science para recuperar estudios prospectivos y aleatorios publicados antes del 12/04/2023. La razón de probabilidad (RP) de cada EA se calculó usando Review Manger 5.4.1. Se evaluó el riesgo de sesgo y se utilizó un metaanálisis basado en modelo de efectos aleatorios para analizar los datos disponibles. Después de una búsqueda sistemática, se identificaron cuatro estudios prospectivos y aleatorios con 237 pacientes. En cuanto a las toxicidades gastrointestinales, los hallazgos indicaron una tendencia hacia una disminución en el riesgo de mucositis (OM) (OR = 0,54, IC 95 %: 0,25-1,14), estreñimiento (OR = 0,87, IC 95 %: 0,49-1,53) y anorexia (OR = 0,99, IC 95 %: 0,32-3,05) y una tendencia creciente en el riesgo de diarrea (OR = 1,48, IC 95 %: 0,79-2,79) entre los pacientes tratados con DE. Sin embargo, no hubo muestras estadísticas significativas. Para toxicidades hematológicas, el riesgo de neutropenia de todos los grados (RP = 0,28; IC del 95 %: 0,14-0,57), leucopenia grado ≥ 2 (RP = 0,43; IC del 95 %: 0,22-0,84), neutropenia grado ≥ 2 (RP = 0,34; IC del 95 %: 0,17-0,67) y neutropenia grado ≥ 3 (RP = 0,28; IC del 95 %: 0,12-0,63) disminuyó significativamente. Ninguna evidencia firme confirmó el efecto preventivo de DE frente a OM o la diarrea. Una DE sería útil previniendo neutropenia y leucopenia.

Influence of experiencing SARS-CoV-2 infection on anxiety levels in Chinese patients undergoing third molar surgery.

Background: In China, most of the citizens experienced SARS-CoV-2 infection since the end of 2022. The Coronavirus disease 2019 (COVID-19) pandemic affected people's physical health and also had a significant impact on mental well-being. The present study aims to discover if the experience of SARS-CoV-2 infection influences patients' anxiety toward third molar surgery in the Chinese population. Materials and methods: The present study took the form of a questionnaire survey. From January 1, 2023, to June 30, 2023, patients who went to the Stomatology Center of China-Japan Friendship Hospital (Beijing, China) for the third molar extraction were included according to the inclusion criteria. The information on COVID-19 infection and the Modified Dental Anxiety Scale (MDAS) was collected. The software SPSS 22.0 was used for the statistical analyses. Results: A total of 574 survey results were harvested in the present study. The infection rate of COVID-19 was 86.6% (p > 0.05). The Average MDAS scores between patients who had been infected with COVID-19 and patients who were never infected were not significantly different (11.65 ± 4.41 vs. 11.42 ± 4.41, p > 0.05). The subgroup analysis was conducted according to the length of time after the recovery of COVID-19 (Model 1), and the highest temperature during the infection (Model 2). In Model 1 and Model 2, the one-way ANOVA test did not find statistical significance between the groups (Model 1 p = 0.114; Model 2 p = 0.481). The MDAS scores in female patients were significantly higher than in male patients (12.29 ± 4.53 vs. 9.91 ± 3.80, p < 0.001). Patients who extracted double teeth got significantly higher MDAS scores than those who extracted single teeth before the surgery (12.03 ± 4.74 vs. 11.24 ± 4.18, p = 0.037). Conclusion: The present study did not establish a significant impact of SARS-CoV-2 infection on the anxiety levels associated with third molar surgery among Chinese patients. The potential long-term biopsychological effects of the virus warrant further investigation.

Hydrogen Embrittlement of 27Cr-4Mo-2Ni Super Ferritic Stainless Steel.

The effect of hydrogen content on the deformation and fracture behavior of 27Cr-4Mo-2Ni super ferritic stainless steel (SFSS) was investigated in this study. It was shown that the plasticity and yield strength of SFSS were very susceptible to hydrogen content. The introduction of hydrogen led to a significant decrease in elongation and a concurrent increase in yield strength. Nevertheless, a critical threshold was identified in the elongation reduction, after which the elongation remained approximately constant even with more hydrogen introduced, while the yield strength exhibited a monotonic increase with increasing hydrogen content within the experimental range, attributed to the pinning effect of the hydrogen Cottrell atmosphere on dislocations. Furthermore, the hydrogen-charged SFSS shows an apparent drop in flow stress after upper yielding and a reduced work hardening rate during the subsequent plastic deformation. The more hydrogen is charged, the more the flow stress drops, and the lower the work hardening rate becomes.

Influence of Different Ratios of DSPE-PEG2k on Ester Prodrug Self-Assembly Nanoparticles for Cell Migration and Proliferation Suppression.

Background: Bufalin (BFL, an active anti-tumor compound derived from toad venom) is limited in its application due to high toxicity and rapid metabolism of the cardiotonic steroid. Ester prodrug self-assembly nanoparticles have shown significant improved effects in addressing the above-mentioned issues. Methods: An ester bond was formed between linoleic acid and bufalin to synthesize linoleic acid-bufalin prodrug (LeB). The self-assembly nanoparticles (LeB-PSNs) containing different mass ratios of DSPE-PEG2k and prodrug (6:4, 7:3, 8:2, 9:1 and 10:0) were prepared via co-precipitation method and defined as 6:4-PSNs, 7:3-PSNs, 8:2-PSNs, 9:1-PSNs and LeB-PSNs, respectively. Further, the characterization (particle size, zeta potential, surface morphology and stability) of the nanoparticles was carried out. Finally, we evaluated the impact of different ratios of DSPE-PEG2k on the hydrolysis rate, cytotoxicity, cellular uptake, cell migration and proliferation suppression potential of the prodrug nanoparticles. Results: The linoleic acid-bufalin prodrug (LeB) was successfully synthesized. Upon the addition of DSPE-PEG2k at different weight ratios, both particle size and polydispersity index (PDI) significantly decreased, while the zeta potential increased remarkably. No significant differences in particle size, PDI and Zeta potential were observed among the 9:1, 8:2 and 7:3 PSNs. Notably, the 8:2 (w/w) DSPE-PEG2k nanoparticles exhibited superior stability, hydrolysis and cellular uptake rates, along with efficient cell cytotoxicity, cell migration and proliferation suppression. Conclusion: These findings indicate that DSPE-PEG2k could improve the performance of BFL prodrug nanoparticles, namely enhancing stability and achieving adaptive drug release by modulating the hydrolysis rate of esterase. This study therefore provides more opportunities for the development of BFL application.

Improving cellular uptake and synergetic anti-tumor effects of magnolol and Brucea javanica oil through self-microemulsion.

OBJECTIVE: Magnolol (MG) and Brucea javanica (L.) Merr. oil (BJO) possess synergetic anti-tumor effects, but have poor water solubility and stability, which results in low oral bioavailability. SIGNIFICANCE: The MG loaded self-microemulsion drug delivery system (MG-SMDDS) with BJO as oil phase component was utilized to improve the cellular uptake and synergetic anti-tumor effects. METHODS: Compatibility study and pseudoternary phase diagram (PTPD) were respectively employed to screen for the composition and proportion of oil phase in the formulation. Central composite design-effect surface method was applied to optimize proportion of each formulation condition. The droplet size, ζ-potential, colloid stability, encapsulation rate (ER) and in vitro dissolution rate of MG-SMDDS were evaluated. Furthermore, cellular uptake and cytotoxicity of the microemulsion on HepG2 cells were assessed. RESULTS: The optimal composition of MG-SMDDS was: MG (9.09%), castor oil (7.40%), BJO (2.47%), Cremophor EL 35 (54.04%) and 1, 2-propanediol (27.01%). The MG-SMDDS exhibited satisfactory droplet size, ζ-potential, colloid stability and ER, as well as faster dissolution rate than free MG. More importantly, SMEDDS containing BJO could enhance the cellular uptake and cytotoxicity of free BJO and free MG on tumor cells. CONCLUSIONS: The BJO self-microemulsion delivery technique can provide an idea for design of oral delivery vehicles based on BJO.

BAIAP2L2 is a novel prognostic biomarker related to migration and invasion of HCC and associated with cuprotosis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its pathophysiological mechanisms remain unknown. IRSp53 family members, such as BAIAP2L1, participate in the progression of multiple tumors. However, the role of BAIAP2L2 in HCC remains unclear. This study comprehensively analyzed the potential role of BAIAP2L2 in HCC using bioinformatic techniques. The expression of BAIAP2L2 in HCC was analyzed using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), and Human Protein Atlas (HPA) databases and in vitro experiments. In addition, the prognostic value of BAIAP2L2 in HCC was analyzed using the TCGA database. TCGA and GEO database were used to analyze the role of BAIAP2L2 in immune features. We also explored the function of BAIAP2L2 in methylation and cuprotosis. The CellMiner database was used to analyze the relationship between BAIAP2L2 expression and drug sensitivity. Our study revealed that BAIAP2L2 is overexpressed in HCC and promotes the migration and invasion of HCC cells. BAIAP2L2 may affect the prognosis of HCC by regulating immunity, methylation, and cuprotosis. BAIAP2L2 is a novel HCC prognostic gene involved in immune infiltration associated with cuprotosis and may be a potential prognosis and therapeutic target for HCC.

Efficacy and Safety of 8 spheres Plus Cisplatin Versus Vinorelbine Plus Cisplatin in Locally Advanced Non-small Cell Lung Cancer.

Background: This study evaluated the efficacy and safety between 8 spheres plus bronchial arterial infusion (BAI) cisplatin and intravenous vinorelbine plus cisplatin as third-line treatments in locally advanced non-small cell lung cancer (NSCLC) patients. Materials and Methods: Totally, 56 locally advanced NSCLC patients with second-line chemotherapy failure were recruited. Then, 28 patients received 8 spheres plus BAI cisplatin treatment, and another 28 patients received intravenous vinorelbine plus cisplatin treatment. Results: In general, 8 spheres plus BAI cisplatin increased objective response rate (57.2% vs. 17.8%, p = 0.002) and disease control rate (78.6% vs. 42.8%, p = 0.003) compared with intravenous vinorelbine plus cisplatin; meanwhile, it also elevated quality of life (QOL) score (46.7 ± 7.1 vs. 41.5 ± 5.2, p = 0.003) compared with intravenous vinorelbine plus cisplatin. Furthermore, 8 spheres plus BAI cisplatin prolonged progression-free survival (PFS) (median [95% confidence interval, CI]: 7.9 [6.3-9.5] months vs. 4.3 [3.5-5.1] months, p < 0.001) and overall survival (OS) (median [95% CI]: 14.6 [11.0-18.2] months vs. 10.5 [10.2-10.8] months, p = 0.029) compared with intravenous vinorelbine plus cisplatin, which was further supported by multivariate Cox's regression analysis (PFS: p < 0.001; OS: p = 0.007). In addition, subgroup analyses revealed that 8 spheres plus BAI cisplatin markedly elevated treatment response, QOL, and survival compared with intravenous vinorelbine plus cisplatin in squamous cell carcinoma patients, but not in adenomatous carcinoma and adenosquamous carcinoma patients. Regarding safety, 8 spheres plus BAI cisplatin exhibited lower rates of gastrointestinal tract complication (p < 0.001) and myelosuppression (p < 0.001) than intravenous vinorelbine plus cisplatin. Conclusions: 8 spheres plus BAI cisplatin displays good efficacy and well-tolerated safety profiles in locally advanced NSCLC patients with second-line chemotherapy failure.

An effective and chemotherapy-free strategy of all-trans retinoic acid and arsenic trioxide for acute promyelocytic leukemia in all risk groups (APL15 trial).

The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has been demonstrated to have comparable effectiveness or better to ATRA and chemotherapy (CHT) in non-high-risk acute promyelocytic leukemia (APL). However, the efficacy of ATRA-ATO compared to ATRA-ATO plus CHT in high-risk APL remains unknown. Here we performed a randomized multi-center non-inferiority phase III study to compare the efficacy of ATRA-ATO and ATRA-ATO plus CHT in newly diagnosed all-risk APL to address this question. Patients were assigned to receive ATRA-ATO for induction, consolidation, and maintenance or ATRA-ATO plus CHT for induction followed by three cycles of consolidation therapy, and maintenance therapy with ATRA-ATO. In the non-CHT group, hydroxyurea was used to control leukocytosis. A total of 128 patients were treated. The complete remission rate was 97% in both groups. The 2-year disease-free, event-free survival rates in the non-CHT group and CHT group in all-risk patients were 98% vs 97%, and 95% vs 92%, respectively (P = 0.62 and P = 0.39, respectively). And they were 94% vs 87%, and 85% vs 78% in the high-risk patients (P = 0.52 and P = 0.44, respectively). This study demonstrated that ATRA-ATO had the same efficacy as the ATRA-ATO plus CHT in the treatment of patients with all-risk APL.

Development and validation of an ECM-related prognostic signature to predict the immune landscape of human hepatocellular carcinoma.

BACKGROUND: The global burden of hepatocellular carcinoma (HCC) is increasing, negatively impacting social health and economies. The discovery of novel and valuable biomarkers for the early diagnosis and therapeutic guidance of HCC is urgently needed. METHODS: Extracellular matrix (ECM)-related gene sets, transcriptome data and mutation profiles were downloaded from the Matrisome Project and The Cancer Genome Atlas (TCGA)-LIHC datasets. Coexpression analysis was initially performed with the aim of identifying ECM-related lncRNAs (r > 0.4, p < 0.001). The screened lncRNAs were subjected to univariate analysis to obtain a series of prognosis-related lncRNA sets, which were incorporated into least absolute selection and shrinkage operator (LASSO) regression for signature establishment. Following the grouping of LIHC samples according to risk score, the correlations between the signature and clinicopathological, tumour immune infiltration, and mutational characteristics as well as therapeutic response were also analysed. lncRNA expression levels used for modelling were finally examined at the cellular and tissue levels by real-time PCR. All analyses were based on R software. RESULTS: AL031985.3 and MKLN1-AS were ultimately identified as signature-related lncRNAs, and both were significantly upregulated in HCC tissue samples and cell lines. The prognostic value of the signature reflected by the AUC value was superior to that of age, sex, grade and stage. Correlation analysis results demonstrated that high-risk groups exhibited significant enrichment of immune cells (DCs, macrophages and Tregs) and increased expression levels of all immune checkpoint genes. Prominent differences in clinicopathological profiles, immune functions, tumour mutation burden (TMB) and drug sensitivity were noted between the two risk groups. CONCLUSIONS: Our signature represents a valuable predictive tool in the prognostic management of HCC patients. Further validation of the mechanisms involved is needed.

Relationship of vitamin D intake, serum 25(OH) D, and solar ultraviolet-B radiation with the risk of gastric cancer: A meta-analysis.

The purpose of this meta-analysis was to investigate whether vitamin D intake, serum 25(OH) D, and solar ultraviolet-B (UVB) radiation have an effect on the incidence of gastric cancer. Keyword searches of online databases were performed from January 2000 to October 2020. A comprehensive analysis was conducted on the relationship of vitamin D intake, serum 25(OH) D level, and UVB radiation with the risk of gastric cancer. A total of 11 articles were included and analyzed. When the highest and lowest intake levels of vitamin D were compared, no significant association was found between vitamin D intake and gastric cancer incidence [effect size (ES): 1, 95% confidence interval (CI): 0.86-1.16, P = 0.983]. The ES of serum 25(OH) D level and gastric cancer incidence was 0.93 (95% CI: 0.77-1.11, P = 0.4), suggesting no relationship between 25(OH) D level and gastric cancer risk. High UVB radiation was associated with lower gastric cancer incidence (ES: 0.86, 95% CI: 0.84-0.89, P = 0) compared with low UVB radiation. Vitamin D intake and serum 25(OH) D level had no relationship with the risk of gastric cancer. However, an inverse association was found between solar UVB radiation and gastric cancer incidence.

Integrated pan-cancer analysis of CSMD2 as a potential prognostic, diagnostic, and immune biomarker.

The protein encoded by CUB and Sushi Multiple Domains 2 (CSMD2) is likely involved in regulating the complement cascade reaction of the immune system. However, current scientific evidence on the comprehensive roles of CSMD2 in pan-cancer is relatively scarce. Therefore, in this study, we explored the transcriptional level of CSMD2 in pan-caner using TCGA, GEO, and International Cancer Genome Consortium databases. Receiver operating characteristic curve analysis was used to investigate the diagnostic efficacy of CSMD2. The Kaplan-Meier Plotter and Oncolnc were used to investigate the correlation between CSMD2 expression and prognosis. Additionally, we analyzed the correlation between epigenetic methylation and CSMD2 expression in various cancers based on UALCAN, as well as, the correlation between CSMD2 and tumor mutational burden (TMB), microsatellite instability (MSI), and tumor neoantigen burden (TNB) in tumors. TIMER2.0 database was employed to investigate the correlation between CSMD2 and immune cells in the tumor microenvironment and immune checkpoints. Based on TISIDB, the correlation between CSMD2 and MHC molecules and immunostimulators was analyzed. Ultimately, we observed with a pan-cancer analysis that CSMD2 was upregulated in most tumors and had moderate to high diagnostic efficiency, and that high expression was closely associated with poor prognosis in patients with tumors. Moreover, hypermethylation of CSMD2 promoter and high levels of m6A methylation regulators were also observed in most cancers. CSMD2 expression was negatively correlated with TMB and MSI in stomach adenocarcinoma (STAD) and stomach and esophageal carcinoma (STES), as well as with tumor mutational burden, microsatellite instability, and TNB in head-neck squamous cell carcinoma (HNSC). In most cancers, CSMD2 might be associated with immune evasion or immunosuppression, as deficient anti-tumor immunity and upregulation of immune checkpoints were also observed in this study. In conclusion, CSMD2 could serve as a promising prognostic, diagnostic and immune biomarker in pan-cancer.

Improving cellular uptake and bioavailability of periplocymarin-linoleic acid prodrug by combining PEGylated liposome.

Periplocymarin (PPM), a cardiac glycoside isolated from Cortex periplocae, has a strong anti-tumor effect against various cancer cells. However, cardiotoxicity and rapid metabolism hinder its clinical applications. In this study, small molecule prodrug was integrated into PEGylated liposome to improve the efficiency of periplocymarin in vivo. The periplocymarin-linoleic acid (PL) prodrug was constructed by conjugating the linoleic acid with PPM via esterification, which was further facilitated to form PEGylated liposome (PL-Lip) through film dispersion. Compared with PL self-assembling nano-prodrug (PL-SNP), PL-Lip showed better colloid stability, sustained drug release kinetics, and enhanced cellular uptake by tumor cells. Notably, PL-Lip performed better than PPM and PL-SNP in terms of tumor distribution and pharmacokinetics, which include bioavailability and half-life. Altogether, the prodrug PEGylated liposome represents a good strategy and method for long-circulating and tumor-targeting delivery of periplocymarin with enhanced clinical application prospect.

Advances in peptides encoded by non-coding RNAs: A cargo in exosome.

The metastasis of malignant tumors determines patient prognosis. This is the main reason for the poor prognosis of patients with cancer and the most challenging aspect of treating malignant tumors. Therefore, it is important to identify early tumor markers and molecules that can predict patient prognosis. However, there are currently no molecular markers with good clinical accuracy and specificity. Many non-coding RNA (ncRNAs)have been identified, which can regulate the process of tumor development at multiple levels. Interestingly, some ncRNAs are translated to produce functional peptides. Exosomes act as signal carriers, are encapsulated in nucleic acids and proteins, and play a messenger role in cell-to-cell communication. Recent studies have identified exosome peptides with potential diagnostic roles. This review aims to provide a theoretical basis for ncRNA-encoded peptides or proteins transported by exosomes and ultimately to provide ideas for further development of new diagnostic and prognostic cancer markers.

Balancing the Risk-Benefit Ratio of Immune Checkpoint Inhibitor and Anti-VEGF Combination Therapy in Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) combined with vascular endothelial growth factor receptor (VEGFR)-targeted therapy and sunitinib monotherapy have been widely applied to metastatic renal cell carcinoma (mRCC), effectiveness and safety data are still lacking. To optimize clinical decision-making, we conducted a systematic review and meta-analysis of published randomized clinical trials to characterize the efficacy and the risk of adverse events (AEs) in patients treated with ICIs plus anti-VEGF therapy. MATERIALS AND METHODS: We used PubMed, EMBASE, and the Cochrane Library to retrieve randomized controlled trials (RCTs) published before March 27, 2021. The efficacy outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The pooled risk ratio (RR) and 95% confidence intervals (CI) of AEs were calculated in the safety analysis. RESULTS: Six RCTs involving 4,227 patients were identified after a systematic search. For OS, ICI and anti-VEGF combination therapy decreased mortality approximately 30% in the intention-to-treat population (ITT) (hazard ratio (HR) = 0.70, 95% CI: 0.57-0.87), but there was no statistical difference in patients evaluated as "favorable" by the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) criteria compared with monotherapy (HR = 0.90, 95% CI: 0.55-1.46, p = 0.66). In terms of PFS, the progression risk for all participants declined 35% (HR = 0.65, 95% CI: 0.50-0.83) and patients evaluated as "poor" by IMDC benefited further (HR = 0.46, 95% CI: 0.36-0.58). No evident divergence was found in age and sex subgroups. The RRs of all-grade hypertension, arthralgia, rash, proteinuria, high-grade (grades 3-5) arthralgia, and proteinuria developed after combination therapy were increased compared with sunitinib. The risk of high-grade hypertension and rash showed no statistical difference. However, the risk of hand-foot skin reaction (HFSR), stomatitis, and dysgeusia decreased in combination therapy groups. CONCLUSIONS: Compared with sunitinib, OS, PFS, and ORR were significantly improved in patients receiving ICI and anti-VEGF combination therapy at the expense of increased specific AEs. More attention should be paid to individualized application of these combination therapies to achieve the best benefit-risk ratio in the clinic. SYSTEMATIC REVIEW REGISTRATION: [https://inplasy.com/] INPLASY: 202130104.

CSMD1 Mutations Are Associated with Increased Mutational Burden, Favorable Prognosis, and Anti-Tumor Immunity in Gastric Cancer.

Tumor mutational burden (TMB) is considered a potential biomarker for predicting the response and effect of immune checkpoint inhibitors (ICIs). To find specific gene mutations related to TMB and the prognosis of patients, the frequently mutated genes in gastric cancer patients from TCGA and ICGC were obtained and the correlation between gene mutation, TMB, and prognosis was analyzed. Furthermore, to clarify whether specific gene mutations can be used as predictive biomarkers of ICIs, a gene set enrichment analysis (GSEA) for immune pathways and an immune infiltration analysis were conducted. The results showed that CUB and Sushi multiple domains 1 (CSMD1) mutation (CSMD1-mut) were associated with higher TMB and better prognosis in patients. The genetic map showed that, compared with wild-type samples, the loss of chromosomes 4q, 5q, 8p, and 9p decreased and the status of microsatellite instability increased in the CSMD1-mut samples. The GSEA analysis showed that immune-related pathways were enriched in the CSMD1-mut samples. The immune infiltration analysis showed that the anti-tumor immune cells were upregulated and that the tumor-promoting immune cells were downregulated in the CSMD1-mut samples. The gene co-expression analysis showed that PD-L1 expression was higher in the CSMD1-mut samples. In summary, CSMD1-mut in gastric cancer was associated with increased TMB and favorable survival and may have potential significance in predicting the efficacy of anti-PD-L1.

Prognostic Role of Tumor Mutational Burden in Cancer Patients Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

PURPOSE: Immunotherapy is regarded as the most promising treatment for cancer. However, immune checkpoint inhibitors (ICIs) are not effective for all patients. Herein, we conducted a systematic review and meta-analysis to explore whether tumor mutational burden (TMB) can be used as a potential prognostic biomarker for cancer patients treated with ICIs. METHODS: We systematically retrieved relevant literature published in the PubMed, Embase, Web of Science, and Cochrane databases up to December 28, 2020. All cohort studies and clinical trials that reported hazard ratios (HRs) for overall (OS) and progression-free survival (PFS), as well as the corresponding 95% confidence intervals (CIs) of high and low TMB patients, were included. All statistical analyses were performed using the R software. RESULTS: Pooled results from a total of 32 studies with 6,131 participants showed significantly increased OS (HR: 0.61, 95% CI: 0.53-0.71; P <0.01) and PFS (HR: 0.51, 95% CI: 0.44-0.60; P <0.01) for the high TMB group receiving ICIs as compared to the low TMB group. Particularly, results were found to be more significant in studies with larger sample sizes (≥30), Western patients, higher TMB cutoff values (≥20 mut/Mb), anti-PD-1 therapy, and when the sample source was tissue and tumor type was either melanoma, small cell lung cancer, or gastric cancer. CONCLUSION: TMB is a promising independent prognostic biomarker for cancer patients receiving ICIs, which could provide a new potential therapeutic strategy for high TMB patients who have failed traditional therapy. Furthermore, consistency in the key aspects of TMB assessment is expected in the future. SYSTEMATIC REVIEW REGISTRATION: [https://www.crd.york.ac.uk/PROSPERO], Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42021229016.

Differential Dermatologic Adverse Events Associated With Checkpoint Inhibitor Monotherapy and Combination Therapy: A Meta-Analysis of Randomized Control Trials.

Background: As immune checkpoint inhibitors (ICIs) transition to the forefront of cancer treatment, a better understanding of immune related adverse events (IRAEs) is essential to promote safe clinical practice. Dermatologic adverse events are the most common IRAEs and can lead to drug withdrawal and decreased quality of life. This meta-analysis aimed to investigate the risk of the most prevalent dermatologic adverse events (pruritus and rash) among various ICI treatment regimens. Methods: A systematic search of electronic databases was performed to identify qualified randomized controlled trials (RCTs). Data for any grade and high grade pruritus and rash were extracted for meta-analysis. Two reviewers independently assessed methodological quality. The relative risk summary and 95% confidence interval were calculated. Results: 50 RCTs involving 29941 patients were analyzed. The risk of pruritus (2.15 and 4.21 relative risk respectively) and rash (1.61 and 3.89 relative risk respectively) developing from CTLA-4 or PD-1/-L1 inhibitor were increased compared to placebo, but this effect was not dose-dependent. PD-1/-L1 plus CTLA-4 inhibitor was associated with increased risk of pruritus (1.76 and 0.98 relative risk respectively) and rash (1.72 and 1.37 relative risk respectively) compared to either monotherapy. Compared with CTLA-4 inhibitor, PD-1/-L1 inhibitor had a significantly decreased risk of pruritus and rash in both monotherapy and combination therapy (0.65 and 0.29 relative risk respectively). No significant difference was found between PD-1/-L1 inhibitor combined with chemotherapy and PD-1/-L1 monotherapy in any grade and high grade rash (0.84 and 1.43 relative risk respectively). In subgroup analyses, PD-1 inhibitor was associated with reduced risk of pruritus and rash compared to PD-L1 inhibitor. Conclusion: Our meta-analysis demonstrates a better safety profile for PD-1/-L1 inhibitor compared to CTLA-4 inhibitor in terms of pruritus and rash among both monotherapy and multiple combination therapies. PD-L1 inhibitor may contribute to an increased risk of pruritus and rash compared to PD-1 inhibitor.

MicroRNA profiles in five pairs of early gastric cancer tissues and adjacent non-cancerous tissues.

Approximately half of the world's gastric cancer cases and deaths occur in China. In addition, the incidence and mortality rates of gastric cancer in Gansu province in China are much higher than the average nationwide levels. The present study investigated microRNA (miRNA/miR) profiles in early gastric cancer (EGC) without specific symptoms. miRNA expression levels in five pairs of EGC tissues and adjacent non-cancerous mucosa tissues of patients from Gansu province in China were analyzed using a miRNA microarray. A total of 47 differentially expressed miRNAs (DEMs) were identified. Subsequently, mRNA expression profiles of three pairs of cancer tissues and adjacent non-cancerous tissues from 3 Asian patients with stage I or stage II gastric cancer (stage I/II; American Joint Committee on Cancer classification, Eighth Edition) were obtained from The Cancer Genome Atlas database, and differentially expressed genes (DEGs) were identified. The target genes of DEMs were filtered from the DEGs using the miRDB database and a miRNA-gene network was constructed. The functions of DEMs were evaluated using the tool for annotations of human miRNAs database, and via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis and Gene Set Enrichment Analysis of the target genes. Finally, survival analyses of DEMs, which were in the miRNA-gene network, was performed. The results suggested that a number of miRNAs, including hsa-let-7a-5p, hsa-miR-27a-3p, hsa-miR-126-5p and hsa-miR-424-5p, may serve critical roles in EGC. The present study could provide a basis for the identification of EGC screening biomarkers. Furthermore, the present study may provide a basis for the exploration of the cause of the high incidence of gastric cancer in Gansu province from the perspective of miRNAs.

Long non-coding RNA LUCAT1 promotes the progression of clear cell renal cell carcinoma via the microRNA-375/YAP1 axis.

Clear cell renal cell carcinoma (ccRCC) is a common renal cell carcinoma with a high mortality rate. Lung cancer-associated transcript 1 (LUCAT1) has been reported to be a potential biomarker of prognosis in human ccRCC. However, the underlying mechanism of the function of LUCAT1 in ccRCC remains poorly understood. The present study aimed to investigate the role and underlying mechanism of LUCAT1 in ccRCC. The expression level of LUCAT1, microRNA-375 (miR-375) and yes-associated protein 1 (YAP1) in ccRCC tissues and cells was detected by reverse transcription-quantitative PCR, and the protein level of YAP1 was detected by western blotting. The effects of LUCAT1 on cell proliferation, migration and invasion were analyzed using Cell Counting Kit-8 and Transwell assays. The association between miR-375 and LUCAT1 or miR-375 and YAP1 was predicted by lncBase Predicted v.2 or TargetScan and verified using dual-luciferase reporter assay. The effect of LUCAT1 on ccRCC progression in vivo was evaluated using a xenograft tumor model. The results revealed that LUCAT1 and YAP1 were upregulated and miR-375 was downregulated in ccRCC tissues and cells. LUCAT1 knockdown suppressed cell proliferation, migration and invasion, which were reversed by the inhibition of miR-375. In addition, YAP1 overexpression attenuated the inhibitory effects of miR-375 overexpression on cell proliferation, migration and invasion. Subsequent experiments suggested that LUCAT1 regulated YAP1 expression by sponging miR-375. Therefore, LUCAT1 exerted its role by regulating the miR-375/YAP1 axis in vitro. Moreover, LUCAT1 knockdown suppressed the growth of ccRCC xenograft tumors in vivo. These results collectively revealed that LUCAT1 promoted the proliferation, migration and invasion of ccRCC by the upregulation of YAP1 via sponging miR-375, which may be used as a potential therapeutic target for ccRCC.